2-Alkylamino- and alkoxy-substituted 2-amino-1,3,4-oxadiazoles-O-Alkyl benzohydroxamate esters replacements retain the desired inhibition and selectivity against MEK (MAP ERK kinase).
This paper reports a second generation MEK inhibitor. The previously reported potent and efficacious MEK inhibitor, PD-184352 (CI-1040), contains an integral hydroxamate moiety. This compound suffered from less than ideal solubility and metabolic stability. An oxadiazole moiety behaves as a bioisostere for the hydroxamate group, leading to a more metabolically stable and efficacious MEK inhibitor.
Warmus
Joseph S
JS
Department of Chemistry, Pfizer Global Research and Development, Ann Arbor, MI 48105, USA. Joseph.Warmus@Pfizer.com
Flamme
Cathlin
C
Zhang
Lu Yan
LY
Barrett
Stephen
S
Bridges
Alexander
A
Chen
Huifen
H
Gowan
Richard
R
Kaufman
Michael
M
Sebolt-Leopold
Judy
J
Leopold
Wilbur
W
Merriman
Ronald
R
Ohren
Jeffrey
J
Pavlovsky
Alexander
A
Przybranowski
Sally
S
Tecle
Haile
H
Valik
Heather
H
Whitehead
Christopher
C
Zhang
Erli
E
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000188:drug therapy; D020650:Combinatorial Chemistry Techniques; D004354:Drug Screening Assays, Antitumor; D004952:Esters; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000187:drug effects; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D000970:Antineoplastic Agents; D001549:Benzamides; D004952:Esters; D006877:Hydroxamic Acids; D010069:Oxadiazoles; D020929:Mitogen-Activated Protein Kinase Kinases